Tumor is a kind of disease with great threat to human health. Benefiting from technological advances of life science research, and in-depth understanding of tumor pathology in the last three decades, breakthrough on research and development of antitumor drugs were obtained. The successful development of various types of novel molecule targeted antitumor drugs has played an important role in improving tumor treatment levels. At present stage, the difficulty of tumor treatment is tumor drug resistance. Heterogeneity and easy mutation characteristics of tumor are the main reasons prone to drug resistance thereof, therefore, it is of great clinical significances to carry out drug research and development according to the mechanism of tumor drug resistance.
Antimetabolite drugs is an important part of antineoplastic drugs, whose market share accounted for 15.75% of the whole hospital antitumor drug market in 2010, ranking third. Antimetabolite antitumor drug is mainly composed of nucleoside drugs, wherein gemcitabine, cytarabine, decitabine, azacitidine, cladribine, fludarabine, nelarabine, etc. are most commonly used.
Gemcitabine is a fluorocytidine analogue, which belongs to cycle-specific antitumor drugs. Gemcitabine acts primarily on DNA synthetic phase, and it also can block the progress from DNA pre-synthetic stage to the DNA synthetic stage in cell cycle. Under the action of deoxycytidine kinase, gemcitabine is converted to the active gemcitabine diphosphate and triphosphate, which thereby inhibits tumor cell division and induces tumor cell apoptosis by affecting DNA synthesis and repair. Gemcitabine is suitable for the treatment of mid-stage and advanced non-small cell lung cancer, locally advanced or metastasized pancreatic carcinoma.
Gemcitabine can be used in the treatment of paclitaxel-resistant and anthraquinones-resistant breast cancer. Studies have shown that over-expression of resistance gene P-gp and MRP is an important reason that related drug resistant tumor cells are sensitive to gemcitabine, and the possible mechanism is that increased expression of deoxycytidine kinase caused by multidrug resistance can improve the accumulation of gemcitabine triphosphate (dFdCTP) in tumor cell, and promote the combination of gemcitabine to DNA strands in tumor cell, thereby increases the drug susceptibility of drug resistant tumor cells.
Current studies of gemcitabine and its derivatives mainly focus on synthesizing compounds of high anti-tumor activity through the modification and alteration on the amine group of cytosine ring. However, there is a shortcoming that it only aims at single-target effect on inhibiting DNA synthesis in tumor cell, multi-target mechanism is not considered to synthesize compounds with high anti-tumor activity because of the objective technical difficulty.